title: 3D QSAR/CoMFA and CoMSIA studies on antileukemic steroidal esters coupled with conformationally flexible nitrogen mustards.
abstract: Thirty-eight antileukemic steroidal esters possessing conformationally flexible nitrogen mustards were studied, and the 3D QSAR/CoMFA and CoMSIA methodologies were applied in order to derive the correlation between their structure and the in vivo antileukemic activity. These compounds show significantly reduced toxicity and possibly increased bioavailability compared to free nitrogen mustards and therefore constitute potent antileukemic drugs. Both the CoMFA and CoMSIA studies gave similar results indicating that the steric effect and the hydrophobic/hydrophilic balance especially in the steroidal part of the molecules probably determined their bioactivity. Of paramount interest is the observation that the orientation of the alkylating part of the SMEs toward the surface of ring B of the steroidal skeleton was related with increased activity. Concerning the steroidal part, the presence of hydrophobic groups in rings B and D was found to be important for enhanced activity. Enhancement of antileukemic potency is further observed if hydrophilic/H-bond acceptor groups are present at the positions 7 and 17 of the steroidal skeleton. Leapfrog simulations provided novel compounds which lead our future synthetic endeavor for obtaining SMEs with optimum bioactivity.
authors.affiliation: Department of Pharmacy, University of Patras, 26500 Rio, Patras, Greece.
authors.forename: Agnes
authors.initials: A
authors.lastname: Kapou
authors.forename: Nikolas-P
authors.initials: NP
authors.lastname: Benetis
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.forename: Sotiris
authors.initials: S
authors.lastname: Nikolaropoulos
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D048088:Informatics; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009588:Nitrogen Mustard Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D055672:Static Electricity; D013256:Steroids / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D013256:Steroids